Modified Project Summary/Abstract Section Major depression is a subjective emotional state resulting in decreased mood, loss of ability to cope with stressful life events and reduced ability to experience pleasure. The incidence of major depression is increasing worldwide, and a significant proportion of patients suffering from major depression have an underlying comorbid condition of an activated innate immune system. Clinical data have already shown that symptoms of depressed mood are elicited by cytokine administration. Also, preclinical models show that physiological stressors, including psychological stress or infection, induce the production of inflammatory cytokines followed by depression-like behaviors. It is now generally accepted that symptoms of depression are associated with systemic inflammation. Negative affect, anhedonia and fatigue are all symptoms of depression that are induced by inflammatory events. However, these criteria possess distinct psychopathological constructs, suggesting discrete inflammation-dependent pathways responsible for specific symptoms. To date, the biological underpinnings of these symptom-dependent pathways have eluded characterization. The experiments in this proposal will build on our discovery that tryptophan is metabolized through divergent indolamine 2,3-dioxygenase (IDO)-dependent pathways that are uniquely responsible for deficits in motivated behavior (anhedonia and fatigue) and induction of negative affect (helplessness/despair). Three overlapping areas will be investigated to define the role of tryptophan metabolism in specific symptoms of depression. In Aim 1, we will use preclinical genetic and pharmacological Ido floxed mouse models to characterize the tryptophan metabolizing pathways necessary for negative affect. In Aim 2, floxed mice will then be used to clarify the role of tryptophan metabolism in motivated behaviors. In Aim 3, we will define the regulation of tryptophan metabolism within specific brain regions relative to specific symptoms of depression, focusing on the striatum and hippocampus. These exciting and novel experiments will be the first to integrate neuroimmune regulation of tryptophan metabolism with specific symptoms of major depression. This effort is the first step toward the development of new targets to treat depression based on symptomology.